The overall goal of the proposed research is to delineate immune mechanisms that can control lentiviral infections. The lentiviral system to be studied is EIAV in horses which has episodes of viremia resulting in fever, anemia, thrombocytopenia and lymphocytic lesions in the liver and other organs. Most horses terminate initial viremia and recurrences to eventually become asymptomatic carriers with very low levels of virus. Data indicating lymphocyte responses control EIAV include the observation that foals with genetically based severe combined immunodeficiency can not control the initial viremia following EIAV infection, in contrast to normal foals, and corticosteroid treatment of EIAV in carriers induces viremia and disease. Immune control of EIAV will be dissected by testing the assumption that CD8+ cytotoxic T lymphocytes (CTL) control EIAV and disease in infected horses. Even though effective vaccines will likely induce several important protective immune functions, a major gap in current knowledge is understanding the in vivo role of lentiviral- specific MHC-restricted CD8+ CTL in controlling infections. Our demonstration of MHC-restricted CD8+ CTL to Env and Gag/PR protein epitopes in unstimulated PBMC from EIAV infected horses provides an opportunity to obtain definitive information on their role in controlling this lentiviral infection. Such data may apply to other lentiviruses including HIV-1 where dissection of the in vivo role of CTL is more difficult. Use of CD8+ CTL from EIAV infected horses will facilitate identification of the immunodominant epitopes recognized during virus control for use in inducing the desired CTL. Finally, questions about the in vivo role of CD8+ CTL can be further evaluated by challenging these immunized horses with homologous and heterologous EIAV, and by determining if CD8+ T lymphocyte depletion will prevent termination of initial viremia in infected horses.